Abstract
Japanese encephalitis virus (JEV), a mosquito-borne zoonotic flavivirus, is an enveloped positive-strand RNA virus that can cause a spectrum of clinical manifestations, ranging from mild febrile illness to severe neuroinvasive disease. Today, several killed and live vaccines are available in different parts of the globe for use in humans to prevent JEV-induced diseases, yet no antivirals are available to treat JEV-associated diseases. Despite the progress made in vaccine research and development, JEV is still a major public health problem in southern, eastern, and southeastern Asia, as well as northern Oceania, with the potential to become an emerging global pathogen. In viral replication, the entry of JEV into the cell is the first step in a cascade of complex interactions between the virus and target cells that is required for the initiation, dissemination, and maintenance of infection. Because this step determines cell/tissue tropism and pathogenesis, it is a promising target for antiviral therapy. JEV entry is mediated by the viral glycoprotein E, which binds virions to the cell surface (attachment), delivers them to endosomes (endocytosis), and catalyzes the fusion between the viral and endosomal membranes (membrane fusion), followed by the release of the viral genome into the cytoplasm (uncoating). In this multistep process, a collection of host factors are involved. In this review, we summarize the current knowledge on the viral and cellular components involved in JEV entry into host cells, with an emphasis on the initial virus-host cell interactions on the cell surface.
Highlights
This aspect of virus research is of particular relevance because viral entry is a common feature essential to the initiation, dissemination, and maintenance of productive infection by all human and animal viruses
Whereas the viral factors involved in Japanese encephalitis virus (JEV) entry are well defined, the host factors that participate in this multistep process remain poorly understood
Identification of the bona fide cell-surface receptor(s) responsible for JEV internalization has been a major challenge in JEV biology, primarily because of a lack of availability of the nonsusceptible cell line that has a block in JEV entry but can fully support the subsequent post-entry steps and is capable of serving as a platform cell line for receptor screening and validation
Summary
Japanese encephalitis virus (JEV) is a member of the genus Flavivirus, family Flaviviridae [1,2]. JEV infection has been detected in field-collected or experimentally inoculated non-Culex mosquitoes, such as Ae. albopictus, Ae. vexans, Armigeres subalbatus, and Mansonia uniformis, and three Anopheles species (An. minimus, An. sinensis, and An. tessellatus), raising the question of whether they can act as potential vectors under certain environmental conditions [50,68,69]. In Asia, domestic pigs and water birds have been recognized as the two most important JEV-amplifying hosts, since they are generally asymptomatic following infection, but develop high-titer viremias sufficient to transmit the virus to engorging mosquitoes [75,76,77,78,79,80,81,82]. Further studies are needed to understand the dynamic interactions between the virus, mosquito vectors, and vertebrate hosts under certain geo-environmental and eco-agricultural conditions [119,120,121]
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